Aryl hydrocarbon receptor nuclear translocator promotes the proliferation and invasion of clear cell renal cell carcinoma cells potentially by affecting the glycolytic pathway

Zhao,Yuxiao; Han,Feng; Zhang,Xufeng; Zhou,Chengjun; Huang,Deqiang

doi:10.3892/ol.2020.11917

Aryl hydrocarbon receptor nuclear translocator promotes the proliferation and invasion of clear cell renal cell carcinoma cells potentially by affecting the glycolytic pathway

Authors:
- Yuxiao Zhao
- Feng Han
- Xufeng Zhang
- Chengjun Zhou
- Deqiang Huang
View Affiliations

Affiliations: Queen Mary School, Nanchang University, Nanchang, Jiangxi 330031, P.R. China, Department of Endocrinology, The People's Hospital of Zhangqiu Area, Jinan, Shandong 250200, P.R. China, Department of Kidney Transplantation, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China, Department of Pathology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China, Department of Gastroenterology, Research Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Published online on: July 29, 2020 https://doi.org/10.3892/ol.2020.11917
Article Number: 56
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Aryl hydrocarbon receptor nuclear translocator (ARNT) is a transcription factor that has been reported to play a vital role in regulating glycolysis, angiogenesis and apoptosis. Recently, ARNT has been reported to a play role in pancreatic‑islet function in type 2 diabetes. However, the role of ARNT in kidney cancer has not yet been investigated. In the present study, ARNT expression was detected in tissues from patients with renal cell carcinoma (RCC) and in RCC cell lines. Oncomine, The Cancer Genome Atlas and cBioPortal were used to investigate the roles of ARNT in RCC. Cell migration and invasion assays were used to explore the molecular mechanisms involved. It was found that ARNT protein expression was elevated both in tissues from patients with clear cell RCC (ccRCC) and in different RCC cell lines. ARNT disruption using siRNA knockdown inhibited the migratory abilities and cell proliferation, potentially by altering the glycolysis pathway in vitro, as evidenced by decreased M2 type acetone kinase, 6‑phosphofructo‑2‑kinase/fructose‑2,6‑bisphosphatase 3 and hexokinase 2 expression. Taken together, the findings in the present study revealed a novel function of ARNT in ccRCC and indicated that ARNT promotes the proliferation and invasion of ccRCC, possibly through changes to the glycolytic pathway.

View Figures

View References

1	Epidemiology, pathology, and pathogenesis of renal cell carcinoma. UpToDate. 2020.
2	Hsieh JJ, Purdue MP, Signoretti S, Swanton C, Albiges L, Schmidinger M, Heng DY, Larkin J and Ficarra V: Renal cell carcinoma. Nat Rev Dis Primers. 3:170092017. View Article : Google Scholar : PubMed/NCBI
3	Lopez-Beltran A, Carrasco JC, Cheng L, Scarpelli M, Kirkali Z and Montironi R: 2009 update on the classification of renal epithelial tumors in adults. Int J Urol. 16:432–443. 2009. View Article : Google Scholar : PubMed/NCBI
4	Vander Heiden MG, Cantley LC and Thompson CB: Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 324:1029–1033. 2009. View Article : Google Scholar : PubMed/NCBI
5	Zheng J: Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review). Oncol Lett. 4:1151–1157. 2012. View Article : Google Scholar : PubMed/NCBI
6	Favaro E, Lord S, Harris AL and Buffa FM: Gene expression and hypoxia in breast cancer. Genome Med. 3:552011. View Article : Google Scholar : PubMed/NCBI
7	Li W, Qiu Y, Hao J, Zhao C, Deng X and Shu G: Dauricine upregulates the chemosensitivity of hepatocellular carcinoma cells: Role of repressing glycolysis via miR-199a:HK2/PKM2 modulation. Food Chem Toxicol. 121:156–165. 2018. View Article : Google Scholar : PubMed/NCBI
8	Huang Y, Lin D and Taniguchi CM: Hypoxia inducible factor (HIF) in the tumor microenvironment: Friend or foe? Sci China Life Sci. 60:1114–1124. 2017. View Article : Google Scholar : PubMed/NCBI
9	McKeown SR: Defining normoxia, physoxia and hypoxia in tumours-implications for treatment response. Br J Radiol. 87:201306762014. View Article : Google Scholar : PubMed/NCBI
10	Chilov D, Camenisch G, Kvietikova I, Ziegler U, Gassmann M and Wenger RH: Induction and nuclear translocation of hypoxia-inducible factor-1 (HIF-1): Heterodimerization with ARNT is not necessary for nuclear accumulation of HIF-1alpha. J Cell Sci. 112:1203–1212. 1999.PubMed/NCBI
11	Mandl M and Depping R: Hypoxia-inducible aryl hydrocarbon receptor nuclear translocator (ARNT) (HIF-1β): Is it a rare exception? Mol Med. 20:215–220. 2014. View Article : Google Scholar : PubMed/NCBI
12	Abel J and Haarmann-Stemmann T: An introduction to the molecular basics of aryl hydrocarbon receptor biology. Biol Chem. 391:1235–1248. 2010. View Article : Google Scholar : PubMed/NCBI
13	Zagórska A and Dulak J: HIF-1: The knowns and unknowns of hypoxia sensing. Acta Biochim Pol. 51:563–585. 2004. View Article : Google Scholar : PubMed/NCBI
14	Gunton JE, Kulkarni RN, Yim S, Okada T, Hawthorne WJ, Tseng YH, Roberson RS, Ricordi C, OConnell PJ, Gonzalez FJ and Kahn CR: Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. Cell. 122:337–349. 2005. View Article : Google Scholar : PubMed/NCBI
15	da Silva Xavier G, Rutter J and Rutter GA: Involvement of Per-Arnt-Sim (PAS) kinase in the stimulation of preproinsulin and pancreatic duodenum homeobox 1 gene expression by glucose. Proc Natl Acad Sci USA. 101:8319–8324. 2004. View Article : Google Scholar
16	Levisetti MG and Polonsky KS: Diabetic pancreatic beta cells ARNT all they should be. Cell Metab. 2:78–80. 2005. View Article : Google Scholar : PubMed/NCBI
17	Fernandez-Salguero PM, Ward JM, Sundberg JP and Gonzalez FJ: Lesions of aryl-hydrocarbon receptor-deficient mice. Vet Pathol. 34:605–614. 1997. View Article : Google Scholar : PubMed/NCBI
18	Huang Q, Sun Y, Ma X, Gao Y, Li X, Niu Y, Zhang X and Chang C: Androgen receptor increases hematogenous metastasis yet decreases lymphatic metastasis of renal cell carcinoma. Nat Commun. 8:9182017. View Article : Google Scholar : PubMed/NCBI
19	Ju L, Zhang X, Deng Y, Han J, Yang J, Chen S, Fang Q, Yang Y and Jia W: Enhanced expression of survivin has distinct roles in adipocyte homeostasis. Cell Death Dis. 8:e25332017. View Article : Google Scholar : PubMed/NCBI
20	Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, et al: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 356:125–134. 2007. View Article : Google Scholar : PubMed/NCBI
21	Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, et al: BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 64:7099–7109. 2004. View Article : Google Scholar : PubMed/NCBI
22	Rankin EB and Giaccia AJ: The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ. 15:678–685. 2008. View Article : Google Scholar : PubMed/NCBI
23	Wang GL, Jiang BH, Rue EA and Semenza GL: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA. 92:5510–5514. 1995. View Article : Google Scholar : PubMed/NCBI
24	Vavilala DT, Ponnaluri VK, Vadlapatla RK, Pal D, Mitra AK and Mukherji M: Honokiol inhibits HIF pathway and hypoxia-induced expression of histone lysine demethylases. Biochem Biophys Res Commun. 422:369–374. 2012. View Article : Google Scholar : PubMed/NCBI
25	Mandl M, Kapeller B, Lieber R and Macfelda K: Hypoxia-inducible factor-1β (HIF-1β) is upregulated in a HIF-1α-dependent manner in 518A2 human melanoma cells under hypoxic conditions. Biochem Biophys Res Commun. 434:166–172. 2013. View Article : Google Scholar : PubMed/NCBI
26	Guidelines for the diagnosis and treatment of renal cancer. National Health Commission of the Peoples Republic of China. 2018.
27	Zelzer E, Levy Y, Kahana C, Shilo BZ, Rubinstein M and Cohen B: Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ARNT. EMBO J. 17:5085–5094. 1998. View Article : Google Scholar : PubMed/NCBI
28	Salceda S, Beck I and Caro J: Absolute requirement of aryl hydrocarbon receptor nuclear translocator protein for gene activation by hypoxia. Arch Biochem Biophys. 334:389–394. 1996. View Article : Google Scholar : PubMed/NCBI
29	Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD and Semenza GL: Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 16:4604–4613. 1996. View Article : Google Scholar : PubMed/NCBI
30	Okino ST, Chichester CH and Whitlock JP Jr: Hypoxia-inducible mammalian gene expression analyzed in vivo at a TATA-driven promoter and at an initiator-driven promoter. J Biol Chem. 273:23837–23843. 1998. View Article : Google Scholar : PubMed/NCBI
31	Bratslavsky G, Sudarshan S, Neckers L and Linehan WM: Pseudohypoxic pathways in renal cell carcinoma. Clin Cancer Res. 13:4667–4671. 2007. View Article : Google Scholar : PubMed/NCBI
32	Myszczyszyn A, Czarnecka AM, Matak D, Szymanski L, Lian F, Kornakiewicz A, Bartnik E, Kukwa W, Kieda C and Szczylik C: The role of hypoxia and cancer stem cells in renal cell carcinoma pathogenesis. Stem Cell Rev Rep. 11:919–943. 2015. View Article : Google Scholar : PubMed/NCBI